Note: Descriptions are shown in the official language in which they were submitted.
CA 02605337 2007-10-17
1
DESCRIPTION
CRYSTAL POLYMORPH OF HYDROXYNOREPHEDRIN DERIVATIVE HYDROCHLORIDE
Technical Field
[0001]-[0003]
The present invention relates to a novel crystal polymorph
of ethyl (-)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-
methylethyl]amino]ethyl]-2,5-dimethyiphenoxyacetate hydrochloride
represented by the following formula (I):
[Chem.1]
Ht) COOEt
HCi
OH H
which has a(33-adrenaline receptor stimulating effect and is useful
as an agent for treating pollakiuria or urinary incontinence.
Background Art
[0004] - [0006]
A hydroxynorephedrine derivative represented by the following
formula (II):
[Chem.2]
Ho ,~COG1Et
à -~~ (II)
N
6H H
has been reported as having an excellent P3-adrenaline receptor
CA 02605337 2007-10-17
2
stimulating effect and being a useful compound as a therapeutic agent
for pollakiuria or urinary incontinence (see Patent reference 1).
[0007]
Heretofore, as a crystalline hydroxynorephedrine derivative
hydrochloride represented by the above formula (I), crystalline forms
A and B have been reported (see Patent reference 2).
[0008]
Particularly, crystals represented by the above formula (I)
wherein the diffraction pattern by the powder X-ray diffractometry
shows characteristic peaks at diffraction angles (20) of 8.9, 10.2,
12 . 9, 14 . 2, 15.6, 18. 4 and 20 . 6(crystalline formA) and the dif.~raction
pattern by the powder X-ray diffractometry shows characteristic peaks
at diffraction angles (20) of 7.3, 10.1, 12.2, 14.6, 15.9, 16.0, 18.7
and 21.8 (crystalline form B) have been reported. However, from the
diffraction chart by the powder X-ray diffractometry, crystals of
the hydroxynorephedrine derivative hydrochloride of the present
invention are novel crystal polymorphs which are different from these
crystals.
[0009]
Patent ref erence 1: International Publication No.W000/02846 pamphlet
Patent reference 2: International Publication No. W003/024916
pamphlet
Disclosure of the Invention
Objects to be solved by the Invention
[0010]
Usually, in a compound which has crystal polymorphs, each
CA 02605337 2007-10-17
3
crystal polymorph has a different property in various ways, and even
if it is the same compound, it may show a different interaction effect.
Especially, in case of medicines, a stable supply of the compound
having the constant crystal polymorph is required so that constant
interaction effects can be always expected. Therefore, it is desired
earnestly to establish a stably manufacturing method to get a compound
having the constant crystal polymorph.
[0011]
In addition, newly finding a new crystal polymorph of a compound
that is useful as a medicament can provide a new opportunity to improve
the performance characteristic of the medicine. For example, this
makes it possible to widen materials for a pharmaceutical researcher
to design the dosage form of the medicine having a desired
characteristic.
[0012]
Therefore, the object of the present invention is to provide
a novel crystal polymorph of the hydroxynoxephedrine derivative
hydrochloride represented by the above formula (I) and a manufacturing
method therefor.
Means of solving the Problems
[0013]
In order to solve the aforementioned problems, as a result
the present inventors have studied earnestly on crystalline
hydroxynorephedrine derivatives hydrochloride represented by the
above formula (I) , the present inventors acquired the knowledge that
CA 02605337 2007-10-17
4
a novel crystal polymorph can be prepared with constant quality
according to using the specific processes that the inventors found
as described below as the s,ituation demands, thereby forming the bases
of the present invention.
[0014]-[0016]
That is, the present invention relates to a crystal represented
by the following formula (I):
[Chem.3]
HO COt3Et
N HC t
!
s 0H H
wherein the diffraction pattern by the powder X-ray diffractometry
has characteristic peaks at diffraction angles (20) of 9.0, 13.6,
18.7, 20.6 and 24.8 (crystalline form C).
[0017]
Crystalline form C of the compound represented by the above
formula (I).can be prepared in the following way.
[0018]
Crystalline form C
The hydrochloride salt of the above compound (II) which can
be prepared by the method described in Example 1 of Patent reference
2 is dissolved by heating in 2 to 3 times the amount of methanol.
After to this reaction mixture is added 15 to 25 times the amount
of ethyl acetate or toluene and it is dissolved by heating, optionally,
10 to 20 % of the solvate is removed under normal pressure. The crystals
which are precipitated under ice-cooling to at room temperature are
11
CA 02605337 2007-10-17
= 5
collected by filtration to obtain crystalline form C.
[0019]
In addition, by the following manufacturing methods, crystal
polymorphs (crystalline form D and crystalline form E) which are
different from crystalline form C can be prepared. Herewith, each
of crystalline forms C, D and E can be prepared with constant quality
according to using each specific process which the inventors found.
[0020]
Crystalline form D
Crystalline form D can be prepared by using as a material ethyl
(-)-2-j4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-
ethyl]amino]ethyl]-2,5-dimethylphenoxyacetate hydrochloride 1/4
hydrate which is prepared by the following method.
[0021]
That is, to ethyl (-) -2- [4- [2- [ [ (7.S, 2R) -2-hydroxy-2-
(4 -hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethyl-
phenoxy]acetate which is prepared by the method described in Patent
reference 1 is added 2 to 5 times the amount of toluene to dissolve.
About 1 equivalent of 30 weight % hydrogen chloride in ethanol is
added to the mixture under ice-cooling, and the reaction mixture is
stirred for 1 to 3 hours at 20 to 30 C. The precipitated crystals
are collected and dried under reduced pressure at about 60 C. By
storing the obtained crystals under an atmosphere of a temperature
between 20 to 30 C and a relative humidity between 50 to 70 % for
one night or more, ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-
hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]-
acetate hydrochloride 1/4 hydrate can be prepared. By removing the
CA 02605337 2007-10-17
6
water of crystallization under a specific condition of heating for
20 to 40 minutes at 60 to 70 C, crystalline form D can be prepared.
The obtained crystal shows the diffraction pattern by the powder
X-ray diffractometry having characteristic peaks at diffraction
angles (20) of 6.5, 11.8, 13.3, 15.1, 17.9 and 20.1.
[0022]
Crystalline form E
Crystalline form E can be obtained by changing the condition
when the water of crystallization is removed from ethyl (-)-2-
[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-
amino]ethyl]-2,5-dimethylphenoxy]acetate hydrochloride 1/4 hydrate
which is prepared by the above-mentioned method. That is, crystalline
form E can be obtained under the condition of heating.ethyl
(-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)--1-methyl-
ethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate hydrochloride 1/4
hydrate which is prepared by the above method at 110 to 130 C for
10 to 20 minutes.
[0023]
As mentioned above, it is important for obtaining crystalline
forms D and E to remove the water of crystallization under each specific
condition: heating the hydrate prepared by the above-mentioned method
at from 60 to 70 C for 20 to 40 minutes (method 1) or at from 110
to 130 C for 10 to 20 minutes (method 2), and crystalline forms D
and E can be first prepared by conducting each of these specific
handlings respectively. Therefore, for example, crystalline forms
D and E can not be prepared only by the manufacturing method described
in Example 1 of Patent reference 2.
CA 02605337 2007-10-17
7
[0024]
Crystalline forms C, D and E which can be obtained by the above
methods can be identified by the following diffraction peaks as shown
in the powder X-ray diffraction charts of Figs.1, 3 and 4.
6 [0025]
That is,
(1) Crystalline form C has characteristic peaks at diffraction
angles (28) of 9.0, 13.6, 18.7, 20.6 and 24.8 degrees as shown in
Fig.l.
(2) Crystalline form D has characteristic peaks at diffraction
angles (20) of 6.5, 11.8, 13.3, 15.1, 17.9 and 20.1 degrees as shown
in Fig.3.
(3) Crystalline form E has characteristic peaks at diffraction
angles (29) of 6.4, 9.8, 12.0, 15.1, 19.9 and 21.3 degrees as shown
in Fig.4.
[0026]
In addition, each crystal polymorph can also be discriminated
by thermogravimetry-differential thermal analysis (TG/DTA) or solid
state C13-NMR spectrum. Each data of the thermogravimetry-
differential thermal analysis (TG/DTA) are shown in Figs. 5 to 8,
and the solid state C13-NMR spectrum are shown in Figs. 9 to 12.
[00273
Crystalline form C which can be obtained by the above method
has a property that polymorphic transformation does not occur during
the storage at a high temperature (60 C and 1 week)- and its chemical
stability is excellent. Moreover, since polymorphic transformation
is not observed at a higher temperature (for example, 140 C), the
CA 02605337 2007-10-17
8
crystal is stable against an exothermic heat which is caused by drug
formulation process (for example, a heat produced by making tablet),
and therefore, a drug formulation can be conducted with the crystalline
form kept constant.
[0028]
The crystal polymorph of the present invention exhibits an
excellent (33-adrenbceptor stimulating effect and relaxes bladder
detrusor muscle and increases the volume of bladder. Therefore,
crystalline form F can be used for the treatment of dysuria such as
pollakiuria or urinary incontinence in nervous pollakuria, neurogenic
bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic
or acute cystitis, prostatic hypertrophy or the like, or idiopathic
pollakiuria, idiopathic urinary incontinence or the like.
[0029]
The crystal polymorph related to the present invention can
be used, if required, in combination with another medicament for the
treatment of dysuria. Examples of such a medicament f or the treatment
dysuria include anticholinergic agents such as oxybutynin
hydrochloride, propiverine hydrochloride, tolterodine, darifenacin,
fesoterodine, trospium chloride, KRP-197, YM-905 and the like; smooth
muscle relaxants such as flavoxate hydrochloride and the like;
(32-adrenoceptor agonists such as clenbuterol hydrochloride,
formoterol fumarate and the like; al-adrenoceptor agonists such as
midodrine hydrochloride, R-450, GW-515524, ABT-866 and the like;
estrogen preparations such as conjugated estrogen, estriol, estradiol
and the like; central nervous system agents such as antiepileptic
agents, antidepressants and the like such as imipramine, reserpine,
CA 02605337 2007-10-17
9
diazepam, carbazapam and the like; neurokinin receptor antagonists
such as TAK-637, SB-223956, AZD-5106 and the like; potassium channel
openers such as capsaicin, resiniferatoxin and the like; vasopressin
2 receptor agonists such as desmopressin, OPC-51803, WAY-141608 and
the like; al-adrenoceptor antagonists such as tamsulosin, urapidil,
naftopidil, silodosin, terazosin, prazosin, alfuzosin, fiduxosin,
AIO-8507L and the like; serotonin receptor antagonists such as
REC-15-3079 and the like; dopamine receptor agonists such as L-dopa
and the like, or dopamine receptor antagonists; antiallergic agents
such as histamine receptor antagonists such as sulplatast tosilate,
norastemizole and the like; NO synthase inhibitors such as
nitroflurbiprofen and the like.
[0030]
The pharmaceutical compositions related to the present
invention can be prepared, for example, by suitably admixing or by
diluting and dissolving crystalline form C with appropriate
pharmaceutical additives such as excipients, disintegrators, binders,
lubricants, diluents, buffers, isotonicities, antiseptics,
moistening agents, emulsifiers, stabilizing agents, dissolving aids
and the like by pharmaceutically well-known method depending on the
formulation.
[00311
In case of using a pharmaceutical composition comprising as
an active ingredient the crystal polymorph of the present invention
in the practical treatment, various dosage forms can be used depending
upon their usages. As the dosage forms, for example, powders, granules,
fine granules, dry syrups, tablets, capsules, injections, solutions,
CA 02605337 2007-10-17
ointments, suppositories, poultices or the like can be illustrated,
and they are orally or parenterally administered.
[0032]
In case of using a pharmaceutical composition of the present
5 invention in the practical treatment, the dosage of crystalline form
C that is an active ingredient is appropriately decided depending
on the age, sex, body weight and degree of symptoms and treatment
of each patient, which is approximately within the range of from 0. 01
to 100 mg per day per adult human in the case of oral administration
10 and approximately within the range of from 0.003 to 30 mg per day
per adult human in the case of parenteral administration, and the
daily dose can be divided into one to several doses per day and
administered suitably.
[0033]
In case of uses of the crystal polymorph related to the present
invention in combination with another medicament for the treatment
of dysuria, pharmaceutical compositions can be formulated by admixing
separately each of active ingredients, or admixing concurrently both
of active ingredients, with pharmaceutically acceptable additives
such as excipients, disintegrators, binders, lubricants, diluents,
buffers, isotonicities, antiseptics, moistening agents, emulsifiers,
stabilizing agents, dissolving aids and the like, and orally or
pareterally administered. In case that pharmaceutical compositions
are separately formulated, the compositions may be mixed together
with an appropriate diluent and administered simultaneously.
Alternatively, separately f ormulatedpharmaceutical compositions may
be administered separately, concurrently or at different intervals.
CA 02605337 2007-10-17
11
Effects of the Invention
[0034]
This time, since crystalline forms C, D and E newly find, they
can provide a new opportunity to improve the performance characteristic
of the medicine. For example, this leads to making it possible to
widen the materials for pharmaceutical researcher to designing the
dosage form of the medicine having a desired characteristic.
Particularly, crystalline form C has an excellent storage stability
wherein it has a property that polymorphic transformation does not
be caused during storage under a high temperature (60 C and 1 week)
and chemical stability is excellent. Moreover since polymorphic
transformation does not be observed under more high temperature (for
example, 140 C), a drug formulation can be conducted by maintaining
the crystalline form constantly against an exothermic heat which is
caused by drug formulation process (for example, heat produced by
making tablet).
Brief description of the drawings
[0035]
Fig. 1 shows powder X-ray diffraction diagram of crystalline
form C obtained in Example 1. The axis of ordinate shows the intensity
of X-rays, and the axis of abscissa shows the angle of the diffraction
(20).
Fig. 2 shows powder X-ray diffraction diagram of a compound
obtained in Reference example 1. The axis of ordinate shows the
intensity of X-rays, and the axis of abscissa shows the angle of the
CA 02605337 2007-10-17
12
diffraction (20).
Fig. 3 shows powder X-ray diffraction diagram of crystalline
form D obtained in Reference example 2. The axis of ordinate shows
the intensity of X-rays, and the axis of abscissa shows the angle
of the diffraction (20).
Fig. 4 shows powder X-ray diffraction diagram of crystalline
form E obtained in Reference example 3. The axis of ordinate shows
the intensity of X-rays, and the axis of abscissa shows the angle
of the diffraction (20).
Fig. 5 shows TG/DTAdata of crystalline form C obtained in Example
1 shown by the TG/DTA curves. The axis of ordinate shows the heat
flow and weight, and the axis of abscissa shows the temperature.
Fig. 6 shows TG/DTA data of a compound obtained in Reference
example 1 shown by the TG/DTA curves. The axis of ordinate shows
theheat flowandweight, andtheaxis of abscissa shows the temperature.
Fig. 7 shows TG/DTA data of crystalline form D obtained in
Reference example 2 shown by the TG/DTA curves. The axis of ordinate
shows the heat flow and weight, and the axis of abscissa shows the
temperature.
Fig. 8 shows TG/DTA data of crystalline form E obtained in
Reference example 3 shown by the TG/DTA curves. The axis of ordinate
shows the heat.flow and weight, and the axis of abscissa shows the
temperature.
Fig. 9 shows solid state C13-NMR spectrum of crystalline form
C obtained in Example 1, the axis of abscissa shows the chemical shifts
(ppm).
Fig. 10 shows solid state C13-NMR spectrum of a compound obtained
CA 02605337 2007-10-17
13
in Reference example 1, the axis of abscissa shows the chemical shifts
(ppm) -
Fig. 11 shows solid state C13-NMR spectrum of crystalline form
D obtained in Reference example 2, the axis of abscissa shows the
chemical shifts (ppm).
Fig. 12 shows solid state C13-NMR spectrum of crystalline form
E obtained in Reference example 3, the axis of abscissa shows the
chemical shifts (ppm).
Best Mode to Put the Invention to Practiae
[0036]
The present invention is further illustrated in more detail
byway of the following Test Examples. However, the present invention
is not limited thereto.
[0037]
The powder X-ray diffraction data of each crystal polymorph
were measured by X-ray diffractometer RINT 2100 ultima+ manufactured
by Rigaku Denki Corporation (measuring conditions; CuK (x rays, 40
kV in X-ray tube voltage, 40 mA in X-ray tube current) . The 20 value
of diffraction pattern by the powder X-ray diffractometry may deviate
in some cases by a factor of about 0. 5 depending on the sample conditions
and measuring conditions. In addition, due to the properties of data,
a total diffraction pattern of the powder X-ray diffractometry is
important for the identification of crystals. The TG/DTAmeasurements
of each crystal polymorph were conducted by thermogravimetry analyzer
(TG/DTA) ThermoPlus 2 series TG8120 manufactured by Rigaku Denki
Corporation (measuring conditions; temperature rising rate
CA 02605337 2007-10-17
14
C/minutes, samplepan (Al), reference (A1203), under a nitrogen
atmosphere). Melting points of each crystal were searched from
differential thermal analysis (DTA) endothermic peak (extrapolation).
The solid state C13-NMR spectrums of each crystal polymorph were
5 measured by AVANCE/DRX500 manufactured by Bruker (measuring
conditions;accumulated counts 512 times, contact time 3msec, repeated
time 5sec, probe 4mm MAS, observed frequency 125. 77Mhz, spinning rate
10000Hz).
10 Examples
[0038]
(Example 1)
Crystalline form C of ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-
hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]-
acetate hydrochloride
Ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-
1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate
hydrochloride (10 g) represented by the above formula (I) which was
prepared by the method described in Example 1 of Patent reference
2 was dissolved in methanol (20 mL) by heating. Ethyl acetate (200
mL) was added to the solution and 38 mL of the solvent was removed
under normal pressure by heating. After the mixture was cooled at
room temperature, the precipitated crystals were collected by
filtration and dried at room temperature in vacuo to give 9.2g of
crystals. The obtained crystals were measured by the powder X-ray
diffraction analysis, and the result is shown in Fig. 1. In addition,
TG/DTA analysis (the result is shown in Fig. 5) was conducted and solid
CA 02605337 2007-10-17
state 13C-NMR spectrum (the result is shown in Fig. 9) was also measured.
[0039]
Diffraction angles (20): 9.0, 13.6, 18.7, 20.6 and 24.8
Melting point: 174 to 177 C
5 [0040]
(Reference example 1)
Ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-
methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate
hydrochloride 1/4 hydrate
10 A mixture of ethyl 2-[4-(2-bromoethyl)-2,5-dimethyl-
phenoxy]acetate (11.3 g), (1R,2S)-p-hydroxynorephedrine (5.0 g),
diisopropylamine (4.54g) and N, N-dimethylformamide (28g) was stirred
at 100 C for 2hrs under a nitrogen atmosphere. After cooling the
reaction mixture to room temperature, ethyl acetate (90 g) and water
15 (38 g) were added to the reaction mixture. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
(45 g) . The combined organic layers were washed with water and brine
successively, and dried over anhydrous sodium sulfate. After the
drying agent was separated by filtration, the solvent was removed
under reduced pressure. Furthermore, the reaction mixture was heated
to remove the solvent by azeotropy with toluene (20 g), and toluene
(28.4 g) was added to the residue. To the resultant solution was
added 30 weight % hydrogen chloride solution in ethanol (3.06 g) under
ice cooling, and the resulting mixture was stirred at 20 C for 2hrs.
The precipitated crystals were collected by filtration, dried at 60 C
for 4 hrs in vacuo and allowed to stand overnight at 25 C and at 60%
relative humidity to give ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-
CA 02605337 2007-10-17
16
2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethyl-
phenoxy]acetate hydrochloride 1/4 hydrate (7.36 g). The obtained
crystals were measured by the powder X-ray diffraction analysis. The
result is shown in Fig.2. In addition, TG/DTA analysis (the result
is shown in Figs. 6) was conducted and solid state 13C-NMR spectrum
(the result is shown in Figs. 10) was also measured. In addition,
the equivalents of hydrate were determined by direct titration of
volumetric titration method of Karl-Fisher method.
[0041]
Diffraction angles (20): 6.5, 11.7, 13.0, 14.0, 16.4, 18.6 and 21.6
Melting point: 174 to 178 C
[0042]
(Reference example 2)
Crystalline form D of ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-
16 hydroxyphenyl)-1-xnethylethyl]amino]ethyl]-2,5-dimethylphenoxy]-
acetate hydrochloride
Ethyl (-) -2- [4- [2- [ [ (1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -
1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate
hydrochloride 1/4 hydrate (10 g) obtained in Reference example 1 was
heated at 65 C for 30 minutes, and the title crystals were obtained.
The obtained crystals were measured by the powder X-ray diffraction
analysxs, and the result was shown in Fig. 3. In addition, TG/DTA
analysis (the result is shown in Figs. 7) was conducted and solid
state 13C-NMR spectrum (the result is shown in Figs. 11) was also
measured.
[0043]
Diffraction angles (20): 6.5, 11.8, 13.3, 15.1, 17.9 and 20.1
CA 02605337 2007-10-17
17
Melting point: 174 to 178 C
[0044]
(Reference example 3)
Crystalline form E of ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-
(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethyl-
phenoxy]acetate hydrochloride
Ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-
phenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate
hydrochloride 1/4 hydrate (10 g) obtained in Reference example 1 was
heated at 120 C for 15 minutes, and the title crystals were obtained.
The obtained crystals were measured by the powder X-ray diffraction
analysis, and the resul t is shown in Fig. 4. Inaddition, TG/DTAanalysis
(the result is shown in Figs. 8) was conducted and solid state 13C-NMR
spectrum (the result is shown in Figs. 12) was also conducted.
[0045]
Diffraction angles (20): 6.4, 9.8, 12.0, 15.1, 19.9 and 21.3
Melting point: 174 to 178 C
[0046]
(Test example 1)
Stability Test J. (60 C)
After ethyl (-) -2- [4- [2- [ [ (1S, 2R) -2-hydroxy-2-- (4-
hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]-
acetate hydrochloride obtained in Example 1 was stored at 60 C for
a week, chemical stability was determined by measuring the residual
percentage of ethyl (-)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyl-
phenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate
hydrochloride by HPLC and polymorphic stability was examined by the
CA 02605337 2007-10-17
18
powder X-ray diffraction measurement . In addition, the change in
appearance was also observed and the results are shown in Table 1.
[0047]
The results are as shown in Table 1. on crystalline form C,
the chemical purity was constant and polymorphic transformation did
not occur. In addition, no change in appearance was observed and
an excellent storage stability was shown.
[0048]
[Table 1]
storage period at start after 1 week
crystal form crystal form C crystal form C
residual percentage 99.6% 99.6%
(chemical purity %)
appearance white white
[0049]
(Test example 2)
Stability Test 2 (140 C)
After heating crystalline form C obtained in Example 1 to 140 C,
change of the crystalline form was examined by the powder X-ray
diffraction measurement. As a result, it was still crystalline form
C even after heating at 140 C, and thus the stability of crystalline
form C at a high temperature was confirmed,
Industrial Applicability
[0050]
This time, since crystalline forms C, D and E were newly found,
they provided a new opportunity f or the development of drug formulation
whose performance characteristic is improved. Particularly, since
CA 02605337 2007-10-17
19
crystalline form C has an excellent storage stability and stability
against heat, it is suitable for formulation.
